As part of a program to prepare new antithrombotic agents, we discovered that unprotected -amino esters can be exclusively C-alkylated. We sought to optimize this process by studying the structures and reactivities of -amino ester enolates. 1 Determining the aggregation state of an enolate, however, is especially difficult due to the high symmetry of the possible aggregatessmonomers, dimers, tetramers, and hexamerssand the spectroscopically opaque Li-O linkage. 2 Herein we describe a spectroscopic method used to assign -amino ester enolates (1) as hexamers in solution.To understand these studies we must briefly digress by describing the dynamic phenomena that are commonly observed for organolithium aggregates but may seem surprising to the nonspecialist. 3 At the lowest attainable NMR probe temperatures (<-100°C), fast processes including solvent exchange, 4 conformational equilibria, 5 and chelate isomerizations 6 can become observable on NMR spectroscopic time scales, with concomitant spectral complexity. The spectra typically simplify on warming above -100°C due to time averaging. Further warming of the probe often leads to a particularly odd effect in which intra-aggregate exchanges of 6 Li nuclei become fast, whereas inter-aggregate exchanges are still slow. 7 Consequently, aggregates that differ by virtue of their aggregation numbers (dimers versus hexamers) or subunit composition (4:2 versus 3:3 mixed hexamers) appear as separate species by 6 Li NMR spectroscopy, but each aggregate manifests a single 6 Li resonance. This combination of rapid intra-aggregate exchange in conjunction with slow inter-aggregate exchange proves critical to the structural assignments.The 6 Li NMR spectrum recorded on [ 6 Li](R)-1 in 9.0 M THF/ toluene at -100°C shows a single resonance, consistent with almost any aggregation state of high symmetry. The 6 Li NMR spectrum recorded on [ 6 Li]rac-1 affords a single resonance at a markedly different chemical shift than ( Figure 1A) show both resonances along with considerable "noise" in the baseline. Additionally, 6 Li spectra recorded on [ 6 -Li, 15 N](S)-1 and [ 6 Li, 15 N]rac-1 show 6 Li-15 N coupling (d, J Li-N ) 3.4 and 3.6 Hz, respectively), confirming chelation as drawn. 8 Varying the probe temperature from -100 to -50°C afforded a single sharp resonance for Figure 1B). The data are consistent with deep-seated structural complexities that simplify by rapid intra-aggregate exchange at elevated temperatures. Furthermore, the relative intensities are independent of the enolate concentration (0.04-0.40 M) and the THF concentration (2.0-9.0 M), indicating that the four species are at the same aggregation and solvation state.We considered models based on homochiral aggregates (R N or S N ) and heterochiral aggregates (R n S N-n ). R n S N-n /R N-n S n and R N / S N refer to pairs of spectroscopically indistinguishable enantiomers. Dimers (R 1 S 1 and R 2 /S 2 ) and tetramers (R 4 /S 4 , R 1 S 3 /R 3 S 1 , and R 2 S 2 ) afford only two and three 6 Li resonances, respectively. ...

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An efficient, asymmetric synthesis of the 5-HT2C agonist vabicaserin in four chemical steps and 54% overall yield from commercially available benzodiazepine was achieved. The synthesis was highlighted by a novel oxidative, multicomponent reaction to affect the quinolinium ring assembly in one step followed by an unprecedented asymmetric hydrogenation of a 3,4-substituted quinolinium salt.

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A number of tin enolates react cleanly with tricarbonylcyclohexadienyliumiron cations, in cases where the use of lithium enolates or silyl enol ethers is problematic; this new carbon-carbon bond-forming reaction allows diastereoselective construction of proximate quaternary centres and provides a key step in a short synthesis of (_+I-trichodiene.